Stable, supersaturated aqueous solutions of saccharide derivatives of the suprarenal cortical hormone series and process of making same



Patented Feb. 14, 1950 UNITED STATES PATENT:OFFICE STABLE, SUPERSATURATED AQUEOUS S LTU'IIONS OF SACCHARIDE DERIVATIVES OF THE SUPRARENAL GORTICAB HOB--- MONE- SERIES AND PROCESS ()F Gr SAME I Karl' Miescher, 'Rielin, and Charles Meystra' Basel, Switzerland; assignors to Ciba' Pharmai ceutical Products'liic rationof 'New'Jersey' Summit, Ji, 2. corpo NoDrawing. Application-November 21 1945, Se; rial Nil. 630,116. Ill Switzerland'December 22,

12 Claims. (01.167977) oXygenwith the exclusion of any crystallization nucleus. That patent explains-in detail the use of members-of the sugar series, such as glucose as organic compounds containing oxygen. Further investigations have now shown that in certain cases, at a low temperature, e. g. 0 C., separations still occur. from; such supersaturated solutions.

It has now been .found that solutions of saccharide derivatives of the suprarenal cortical hormone series of U. S. patent application No." 490,536, filed June ll, 1948 (now Patent 'No'. 2311,6311... canflbemgiven. practically unlimited stability .bythe .use-.of amides oflower mono carboxylic. acids. as. organic compounds containing oxygen. It hasalsobeenfound that by'the further addition of.a.sugar,wsuch-as glucose, the local compatibility in the case of injections of the solution can be increased.

As saccharide derivatives of the suprarenal cortical hormone series there are used, for example, the compounds described in the patent referred to above, and as amides of lower monocarboxylic acids, for example, acetamide, propionamide, butyramide, isovaleramide, or mixtures thereof.

The resulting solutions are intended for therapeutic use.

The following examples illustrate the invention, but are not to be regarded as limiting it in any way, the parts being by weight:

Example 1 1 part of ,B-d-glucoside of desoxycorticosterone is dissolved in 100 parts of an aqueous acetamide solution of per cent. strength by heating on the water bath. Kept in sealed ampules, the clear, supersaturated solution remains completely dissolved, even at a temperature of 0 C.

These ampules may be sterilized at 100 C. without decomposition of the glucoside. Upon dilution with water or blood serum no precipitation occurs.

Example 2 1 part of B-d-glucoside of desoxycorticosterone, 10 parts of acetamide, 10 parts of d-glucose and 100 parts of water are h'eated together on the water-bath until completely dissolved. crystals will sepa'r'ateg: not even at 0 C.

Analogously, solutions of other glucosides of desoxycorticosterone can" be made, for example of thelactoside or' maltoside.

glucoside of'desoxycorticosterone, there may as Instead of the well be used successfullyglucosides of other compounds of the suprarenal cortical hormone series, suchas of corticosterone, dehydrocorticosterone, and the like.

Equally stablesolutions are'obtained by using, instead of aeetamide, other amides of lower monocarboxylic acids, for example propionamide or mixtures of acetamide and propionarnide.

What we claim is:

tive .of thesupraren'al cortical hormone series,

which comprises dissolving the said saccharide' derivative in an aqueous solution containing an amide 'of a lower fatty acid in a concentration sufiicient' 'toieffect stabilization of the solution against the formation of a crystallization nucleus, and in a physiological-1y inert proportion, the fatty acid amide content ofthe aqueous solution being about 10%.

2. A process for the manufacture of a stable, supersaturated solution of a saccharide derivative of the suprarenal cortical hormone series, which comprises dissolving the said saccharide derivative in an aqueous solution containing a physiologically inert proportion of glucose and of an amide of a lower fatty acid, the latter being present in a concentration sufficient to effect stabilization of the solution against the formation of a crystallization nucleus, the glucose content of the said aqueous solution and. the fatty acid amide content of said solution being each about 10%.

3. A process for the manufacture of a stable, supersaturated solution of a saccharide derivative of the suprarenal cortical hormone series, which comprises dissolving the said saccharide derivative in an aqueous solution containing a mixture of lower fatty acid amides in a concentration sufficient to effect stabilization of the solution against the formation of a'crystallization nucleus, and in a physiologically inert proportion, the lower fatty acid amides content of the said aqueous solution being about 10%.

4. A process for the manufacture of a stable, supersaturated solution of a saccharide derivative of the suprarenal cortical hormone series, which comprises dissolving the said saccharide derivative ah aqueous solution. containing a physiologically inert proportion of glucose and of a mixture of lower fatty acid amides, the latter being present in a concentration sufficient to effect stabilization of thesolution against the formation of a crystallization 'nucleus,'the glucose content of the said aqueous solution and the fatty acid amides content of said solution being each about 5. A process for the manufacture of a stable, supersaturated solution of a glucosideof desoxycorticosterone, which comprises dissolving the said saccharide derivative in an aqueous solution containing acetamide in a concentration sufiicient to effect stabilization of the solution against the formation of a crystallization nucleus, and in a physiologically inert proportion, the acetamide content of the aqueous solution being about 10%.

6. A process for the manufacture of a stable, supersaturated solution of a glucoside of desoxycorticosterone, which comprises dissolving the said saccharide derivative in an aqueous solution containing a physiologically inert proportion of glucose and of acetamide, the latter being present in a concentration sufiicient to effect stabilization of the soltuion against the formation of a crystallization nucleus, the glucose content and the acetamide content of the said aqueous solution each being about 10%.

7. A stable, supersaturated aqueous solution of a saccharide derivative of the suprarenal cortical hormone series containing a physiologically inert proportion of an amide of a lower fatty acid in a concentration suflicient to efiect stabilization of the solution against the formation of a crystallization nucleus, the lower fatty acid amide content of the said aqueous solution being about 10%.

,8. A stable, supersaturated aqueous solution of a saccharide derivative of the suprarenal cortical hormone series containing a physiologically inert proportion of glucose and of an amide of a lower fatty acid in a concentration sufiicient to effect stabilization of the solution against the formation of a crystallizationnucleus, the glucose content of the said solution and the lower fatty acid amide content of the said solution each being about 10%.

9. A stable, supersaturated aqueous solution of a saccharide derivative of the suprarenal cortical hormone series containing a physiologically inert proportion of a mixture of lower fatty acid amides in a concentration sufficient to effect stabilization of the solution against the formation of a crystallization nucleus, the lower fatty acid amides content of the said aqueous solution being about 10%.

10. A stable, supersaturated aqueous solution of a saccharide derivative of the suprarenal cortical hormone series containing a physiologically REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 1,658,122 Giinzler Feb. 7, 1928 1,921,722 Berendes Aug. 3, 1933 2,067,317 Gruber Jan. 12, 1937 2,270,379 Miescher Jan. 20, 1942 2,289,050 Schinder July 7, 1942 2,411,631 Miescher Nov. 26, 1946 

11. A STABLE, SUPERSATURATED AQUEOUS SOLUTION OF A GLUCOSIDE OF DESOXYCORTICOSTERONE CONTAINING ABOUT 10% OF ACETAMIDE. 